首页|Upacicalcet Is a Novel Secondary Hyperparathyroidism Drug that Targets the Amino Acid Binding Site of Calcium-Sensing Receptor
Upacicalcet Is a Novel Secondary Hyperparathyroidism Drug that Targets the Amino Acid Binding Site of Calcium-Sensing Receptor
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NSTL
Amer Soc Pharmacology Experimental Therapeutics
The human calcium-sensing receptor (CaSR) is a G protein-coupled receptor that maintains extracellular Ca21 homeostasis by regulating the secretion of parathyroid hormone. Upacicalcet is a novel positive allosteric modulator of CaSR that is used for the treatment of secondary hyperparathyroidism. In the present study, to clarify the binding site of upacicalcet to CaSR, we conducted binding studies and agonistic activity studies in HEK-293T cells expressing human CaSR (intact and mutant) and an in silico docking-simulation analysis. As a result, upacicalcet competed with L-tryptophan and was thought to affect the amino acid binding site. In addition, the effects of substitutions at the amino acid binding site on the binding abilities to upacicalcet as well as the effects on receptor function as measured using inositol-1 mono-phosphate accumulation were examined. Upacicalcet interacted with several CaSR residues that constitute the amino acid binding site. Based on these results, we performed an in silico analysis and obtained a binding mode, consistent with the in vitro study results. Our study revealed that upacicalcet is a novel secondary hyperparathyroidism drug that targets the amino acid binding site of CaSR. Upacicalcet is expected to become a new treatment option for secondary hyperparathyroidism because the binding site differs from that of conventional drugs; consequently, it may be effective for patients who are not sensitive to conventional drugs, and it may have a superior safety profile.
NSTL
Amer Soc Pharmacology Experimental Therapeutics
